Musculoskeletal and connective tissue inflammations are common diseases affecting a large human population. Some commonly seen musculoskeletal and connective tissue inflammations include osteoarthritis and associated articular and periarticular inflammations, and non-articular Rheumatism including capsulitis, tendonitis, fibrositis, and periarticular inflammations.
Osteoarthritis is the most common type of arthritis, especially among older people. Osteoarthritis is a joint disease that mostly affects the cartilage. Cartilage is the slippery tissue that covers the ends of bones in a joint. Healthy cartilage allows bones to glide over one another. It also absorbs energy from the shock of physical movement. In osteoarthritis, the surface layer of cartilage breaks down and wears away. This allows bones under the cartilage to rub together, causing pain, swelling, and loss of motion of the joint. Over time, the joint may lose its normal shape. Also, bone spurs may grow on the edges of the joint. Bits of bone or cartilage can break off and float inside the joint space. This causes more pain and damage. People with osteoarthritis usually have joint pain and limited movement. Unlike some other forms of arthritis, osteoarthritis only affects joints, and not internal organs.
Osteoarthritis is one of the most frequent causes of physical disability among adults. Some younger people get osteoarthritis from a joint injury, but osteoarthritis most often occurs in older people. In fact, by age 65, more than half of the population has x-ray evidence of osteoarthritis in at least one joint. Since the number of older people is increasing, so is the number of people with osteoarthritis. Both men and women have the disease.
Existing osteoarthritis treatment approaches include exercise, medicines, rest and joint care, surgery, pain relief techniques, alternative therapies, and weight control. The commonly used medicines in treating osteoarthritis include nonsteroidal anti-inflammatory drugs (NSAIDs), for example, diclofenac (Voveran® gel, tablet) aspirin, ibuprofen (Advil®, Motrin® IB), naproxen sodium (Aleve®), ketoprofen; topical pain-relieving creams, rubs, and sprays (for example, capsaicin cream) applied directly to the skin; corticosteroids, powerful anti-inflammatory hormones made naturally in the body or man made for use as drugs, typically injected into affected joints to relieve pain temporarily; and hyaluronic acid, a new medicine for joint injection, used to treat osteoarthritis of the knee. Surgery may be performed to resurface (smooth out) bones, reposition bones, and replace joints. For some people, surgery helps relieve the pain and disability of osteoarthritis. Osteoarthritis is a chronic disease. Although various medications have been used for treating the disease, they are not effective for long term control and prevention.
Many of the musculoskeletal and connective tissue inflammations are chronic and cause chronic regional pain and loss of functionality of affected areas.
Diclofenac is one of the routinely prescribed anti-inflammatory agents available for the management of musculoskeletal and connective tissue inflammations. It is marketed as injection, oral immediate release tablets, sustained release tablets and conventional topical formulations. The drug is almost completely absorbed after oral administration but is subjected to 50% hepatic first-pass metabolism.
Although a major portion of commercial diclofenac is available in the form of oral medications, the drug causes serious adverse effects in the gastrointestinal tract. Gastrointestinal (GI) bleeding and ulcerations are quite common due to oral diclofenac. Therefore, topical preparations like creams; ointments for external application are being widely used. However, since diclofenac and its salts are scarcely absorbed percutaneously and thereby require higher quantity to be applied topically thus leading to increased frequency of application also. This leads to patient incompliance.
U.S. Pat. No. 5,629,021 relates to micellar nanoparticles and methods of their production.
U.S. Patent Publication No. 2010/0029781 discloses a method of preparing a solvent-microparticle (SMP) topical gel formulation comprising a bioactive drug wherein the formulation comprises the drug dissolved in a liquid and the drug in a microparticulate solid form dispersed in the liquid.
U.S. Pat. No. 5,894,019 discloses topical compositions comprising lipid and essentially free of emulsifiers and surfactants.
European Patent No. EP 1536836 B1 discloses conventional topical emulsion gel of diclofenac sodium.
European Patent No. EP 506197 B1 discloses an aqueous suspension of solid lipid nanoparticles for topical use.
European Patent No. EP 0671903 B1 discloses topical compositions in the form of submicron oil spheres.
International (PCT) Publication No. 2008/051186 describes nanoemulsion compositions having anti-inflammatory activity.
Clinical evidence suggests that topically applied non-steroidal antiinflammatory drugs (NSAIDs) are safer than and at least as efficacious as oral NSAIDs in the treatment of rheumatic diseases. Adverse drug reactions after topical administration of NSAID use are rare when compared to the incidence of serious GI events associated with oral NSAIDs. However, formulation may have a dramatic impact on depth of penetration at the site of application, retention of drug molecules within the layers of skin, concentrations achieved in the muscle tissue, synovial fluid and in systemic circulation.
Most of the topical preparations contain vehicles comprising permeation enhancers, solvents, and high amount of surfactants to achieve these goals. But use of these agents is harmful, especially in chronic application, as many of them are irritants. Therefore, a need to develop such topical preparations which does not involve use of such agents as described above to facilitate drug permeation through the skin, and still leads to excellent photostability, greater permeability, and improved bioavailability resulting in enhanced therapeutic pharmacodynamic activity is sought.
Thus, it is apparent that there still is a strong need for improved medications of diclofenac that can effectively treat musculoskeletal and connective issue pain or inflammations and related symptoms. A medication that can provide a long term control of musculoskeletal and connective tissue inflammations, inhibit further progress of existing conditions, and prevent reoccurrence of acute symptoms will have important medical significance for millions of people who suffer from these diseases.